There has been a remarkable development of study of vitamin D since 1958 when 25-hydroxy vitamin D.sub.3 was found as an activated metabolite of vitamin D.sub.3 and more extensively since 1971 when 1.alpha.,25-dihydroxy vitamin D.sub.3 which is by far the most activated substance of all the known metabolites of vitamin D.sub.3 was discovered. (See the following reference papers.)
Reference Paper 1: H. F. DeLuca et al., Ann. Rev. Biochem., vol.45, p.631, 1976 PA0 Reference Paper 2: H. F. DeLuca, Nutr. Rev., vol.37, p.161, 1979 PA0 Reference Paper 3: D. E. M. Lawson, "vitamin D", Academic Press, Inc., New York, 1978 PA0 Reference Paper 4: A. W. Norman, "Vitamin D, The Calcium Homeostasis Steroid Hormon", Academic Press, Inc., New York, 1979 PA0 It has been known for some time that 1.alpha., 25-dihydroxy vitamin D.sub.3 is particularly effective for small intestine and bone and more recently there was a report evidencing that kidney, pancreas, pituitary body, thymus, thyroid, skin, mammary gland, lymphocyte and many other tissues and organs have receptors for the chemical. (See Reference Paper 5 below.) Likewise, it has also been proved that various tumorous cells such as malignant melanoma celss (see Reference Paper 6 below), breast cancer cells (see Reference Paper 7 below), osteogenic sarcoma cells (see Reference Paper 8 below) and myeloid leukemia cells (see Reference Paper 9 below) have receptors. PA0 Reference Paper 5: H. F. DeLuca et al., Proc. Natl.Acas. Sci. USA, vol.77, p.1149, 1980 PA0 Reference Paper 6: K. Colston et al., Endocrinology, vol. 108, p.1083, 1981 PA0 Reference Paper 7: H. F. Freake et al., Biochem.Biophys. Res.Commun., vol.101, p.1131, 1981 PA0 Reference Paper 8: S. C. Mnolagas et al., J.Biol.Chem., vol.255, p.4414, 1980 PA0 Reference Paper 9: T. Suda et al., Biochem.J., vol.204, p.713, 1982 PA0 Reference Paper 10: T. Suda et al., Proc.Natl,Acad.Sci., USA, vol.78, p.4990 PA0 Reference Paper 11: E. Abe, Vitamin, vol.59, p.418, 1985 PA0 Reference Paper 12: C. Kaneko, Organic Synthetic Chemistry, vol.33, p.75, 1975, etc. PA0 Reference Paper 13: H. F. DeLuca et al., J. Org. Chem., vol.45, p.3253, 1980 etc. PA0 Reference Paper 14: R. H. Hesse et al., J. Org. Chem., vol.51, p.1635, p.4819, 1986 etc. PA0 Reference Paper 15: W. H. Okamura et al., Tetrahedron Letters, vol.28, p.2095, 1987 PA0 Reference Paper 16: E. G. Baggiolini et al., J.Org.Chem., vol.51, p.3098, 1986 PA0 Reference Paper 17: L. Castedo et al., Tetrahedron Letters, vol. 28, p. 2099, 1987 etc. PA0 Reference Paper 18: Y. Mazur et al., J. Am. Chem. Soc., vol.97, p.6249, 1979 PA0 Reference Paper 19: W. H. Okamura et al., J. Org. Chem., vol.48, p.1414, 1983 PA0 Reference Paper 20: Y. Wang et al., Acta. Chem. Sin., vol.24, p.126, 1958) PA0 Reference Paper 21: H. F. DeLuca et al., Japanese Patent Application No. 59-93130
Since then extensive reseaches have been done in the fields of biochemistry, organic chemistry, and medicine through cooperation of researchers of these and other research areas. As a result of the research efforts, 1.alpha., 25-dihydroxy vitamin D.sub.3 which is an activated type vitamin D.sub.3 and its homologue 1.alpha., 25-hydroxy vitamin D.sub.3 were developed as medicines for kidney diseases, bone diseases and thyroidal disorders. (See the following reference papers.)
Particularly the fact that 1.alpha., 25-dihydroxy vitamin D.sub.3 suppresses proliferation of myeloid leukemia cells and accelerates differentiation of cells (see Reference Paper 10 below) and that there is a certain relationship between activated type vitamin D and the immune system of the body suggests potential and encouraging applications of the chemical (see Reference Paper 11 below).
Since the 1.alpha.-hydroxy component of activated type vitamin D and its various derivatives is considered to play a vital and fundamental role in the physiological effects of these chemicals, many of laboratories and research institutes all over the world have been concentrating their efforts on the study of the component and consequently a number of achievements have been reported in the research field. Some of the examples of the achievements of the researches include,
1) a photochemical method of obtaining desired vitamin D derivaties in which 1.alpha.-hydroxidated steroid is synthesized in the first place and then it is converted to the corresponding 1.alpha.-hydroxy-5,7-dienesterol derivative which is used as material for the vitamin derivative,
2) a method with which a vitamin D derivative is converted to a 3,5-cyclovitamin derivate and then combined with allylic acid at position C(1), the product being converted again to obtain the desired vitamin D derivative,
3) a method with which vitamin D is temporarily converted to transvitamin D, which is combined with allylic acid at position C(1), the product being photochemically reconverted to vitamin D and
4) a method with which a fragment corresponding to an A-ring portion and having a hydroxyl group at position C(1) is synthesized with a view to total synthesis and then combined with a fragment that corresponds to a D-ring portion to obtain the aimed compound.
Of the above cited methods, the method 1) is most popularly used as it is a relatively practical one, although it comprises a number of steps required to introduce a hydroxyl group to position 1.alpha. and its stereo- and positional selectivity is not very good, making the overall process rather inefficient as a number of steps are further required to obtain the aimed final vitamin D derivative by means of conversion. On the other hand, the method 2) allows use of any known process for conversion from vitamin D to 3,5-cyclovitamin D with a high yield (see the paper below).
The reaction with allylic acid of the method 2) above has a high stereoselectivity although it can not be conducted with a high yield as oxo compounds are brought forth at position C(1) as by-product at a significant level. Moreover, the method (b) is accompanied by other problems such as the fact that by-products including transvitamin D which are not easily separable from the aimed 1.alpha.-hydroxy vitamin D are produced in the solvolysis of the 1.alpha.-hydroxy compound of the product.
The method 3) can not be conducted without problems either because it entails a low yield at the stage of oxidzation or because a photochemical process is required for conversion of the oxidized compound into vitamin D, although it has a high yield of conversion from vitamin D to transvitamin D.
Finally, the method 4) is practically not a satisfactory one in view of the fact that it requires a number of steps throughout the whole process.
As is apparent from the above description, any existing and prevalent methods are not satisfactory in view of practical applications and development of more effective and efficient methods is desired.
The inventor of the present invention has, with due regard to these problems, carried out an extensive research for development of an effective synthetic method for producing significant intermediate compounds that can be combined with allylic acid at position C(1) for production of vitamin D and finally come to develop an effective and efficient method which is based on a concept and procedures completely different from those of any existing methods and in which aimed vitamin D.sub.2, vitamin D.sub.3, activated type vitamin D.sub.2, activated type vitamin D.sub.3 or any of their derivatives is obtained from 7,8-dihydroxy vitamin D.sub.2, D.sub.3 or any of their derivatives by means of a reducing elimination technique involving a cyclic ortho-ester or a thiocarbonate of a 7,8-dihydroxy compound as an intermidiate compound or an elimination technique utilizing a reducing metal such as titanium.